Blockade of endogenous opiates released in circulatory shock may improve cardiovascular function (Vargish et al., Circ. Shock 7:31-38, 1980). In addition, our preliminary studies indicate that during hemorrhagic shock of anesthetized cats, endogenous opiates and a spinal tryptaminergic system act to limit sympathetic preganglionic activity and to effectively depress heart rate, myocardial contractility, and vasoconstriction. In the proposed research, we seek to characterize the interactions of the opiate and serotonergic system during hemorrhage with regard to possible spinal and supraspinal neuronal pathways and pharmacologic interventions which may modify the activity of the systems. We shall determine the myocardial contractility, i.e., maximum dP/dt of the left ventricle, heart rate, mean arterial blood pressure, and the multiunit activity of the caudal raphe neurons and the greater splanchnic nerve of cats before, during and after a standardized hemorrhagic shock protocol. We shall determine plasma activities of catecholamines and serotonin periodically during each experiment and the tissue content of these in samples of spinal cord, supraspinal structures and heart excised at the conclusion of each experiment. In hemmorrhaged animals we shall assume the pressor response to opiate blockade with naloxone is indicative of opiate receptor activation during shock. The effect of opiate blockade will be assessed in hemorrhaged cats in which the activity of the tryptaminergic system is modified by: (a) electrolytic lesion of the caudal raphe neurons, (b) administration of methysergide in the subarachnoid space at T4 of the spinal cord, (c) depletion of serotonin with parachlorophenylalanine or (d) increase of central serotonin stores with tryptophan loading. The results of these experiments will provide new information on systems which are activated and regulate blood pressure in circulatory shock. Moreover, the response of the cardiovascular system to pharmacological manipulation of the opiate and tryptaminergic system may provide the rationale for specific therapeutic interventions in the treatment of circulatory shock.